Multifunctional nanoscopy for imaging cells

Abstract

Disclosed herein is an apparatus for sensing characteristics of an object. In a preferred embodiment, the apparatus comprises an array, wherein the array comprises a plurality of nanoscale hybrid semiconductor / metal devices which are in proximity to an object, each hybrid semiconductor / metal device being configured to produce a voltage in response to a perturbation, wherein the produced voltage is indicative of a characteristic of the object. Any of a variety of nanoscale EXX sensors can be selected as the hybrid semiconductor / metal devices in the array. With such an array, ultra high resolution images of nanoscopic resolution can be generated of objects such as living cells, wherein the images are indicative of a variety of cell biologic processes.

Description

CROSS-REFERENCE AND PRIORITY CLAIM TO RELATED PATENT APPLICATION[0001]This patent application claims priority to U.S. provisional patent application 60 / 821,040, filed Aug. 1, 2006, and entitled “Multifunctional Nanoscopy for Imaging Cells”, the entire disclosure of which is incorporated herein by reference.STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT[0002]This invention was made with government support under NIH grants such as EB002168, HL042950, and CO-27031 awarded by the National Institutes of Health (NIH). The government may have certain rights in the inventionFIELD OF THE INVENTION[0003]The field of this invention relates generally to techniques for measuring characteristics of an object (such as the cell function and structure of one or more living cells) on a nanoscale via an array of integrated nanosensors that are responsive to various perturbations such as acoustic waves, light, or electric charge.BACKGROUND AND SUMMARY OF THE INVENTION[0004]The rapid ac...

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Benefits of technology

[0004]The rapid acquisition and analysis of high volumes of data in biological samples had its advent in the early days of the human genome sequencing project. Microarray technology has facilitated the interrogation of large numbers of samples for biologically relevant patterns in a variety of physiological, drug-induced or clinically relevant cellular states. A challenge has now presented itself with respect to how these large volumes of information can be integrated into an accurate model of cellular behavior and processes. For example, information relating the effect of a drug to the extent and duration of apoptosis in cancer cells would be invaluable information in a screen for cancer drugs. Similarly, information of cytoskeletal changes leading to invasiveness would greatly streamline the development of an efficient anti-angiogenic drug strategy.

[0011]Many protocols for generating data are already well developed in their respective disciplines, from quantitative Polymerase Chain Reaction (PCR), to flow cytometry, to antibody staining. The methods for acquisition of this data, such as different types of optical microscopy, have already undergone extensive development. Perhaps the most important image acquisition methods for HCS relate to cellular imaging, including drug effect assays for cytotoxicity, apoptosis, cell proliferation, and nucleocytoplasmic transport. Frequently, these approaches utilize cell sensors based on fluorescent proteins and dyes, and thus provide researchers with an ability to screen drugs and to answer more complex biological questions such as target identification and validation and to investigate gene and protein function.

[0012]In an effort to fill a need in the art for improved cellular imaging techniques, the inventors herein disclose a new, inexpensive, and easy-to-use imaging technology suitable for simultaneous capture of multiple measurements from individual cells that will enable molecular colocalization, metabolic state and motility assessment, and determination of cell cycle, texture, and morphology. This technology will be capable of not only HCS, but also permit selection of single cells for subsequent high-resolution imaging based on the outputs of the HCS. By increasing the analytical resolution to assess the sub-cellular state in vivo, the inventors herein hope to increase biological resolution by providing a means to follow the location, timing, and interdependence of biological events within cells in a culture.

[0015]The inventors herein believe that the use of nanoscale EAC sensors and nanoscale EPC sensors in an imaging array will provide improved imaging resolution, improved signal-to-noise ratio (SNR), and higher bandwidth than conventional ultrasonic or other modes of detectors. Accordingly, the use of an array having a plurality of nanoscale EAC sensors and / or a plurality of nanoscale EPC sensors can be used for a myriad of applications, including but not limited to in vitro cell imaging, in vivo invasive catheter-based applications for medical imaging, endoscopic imaging for gastrointestinal, prostate, or urethral / bladder / ureteral applications, transdermal medical imaging for disease characterization, detection of abnormal cells in serum samples, acoustic imaging, pressure sensing in nanofluidics, and blood pressure monitoring inside small vessels.

[0017]The inventors herein further believe that the use of nanoscale EEC sensors in an imaging array will produce ultra high resolution images of electric charge distribution over the surface of one or more living cells, a result that can provide valuable information for monitoring cancer metastasis and targeted drug delivery, particularly so when a series of such images are taken over time to track the progression of the cell's electric charge over time. The inventors herein believe that the nanoscale EEC sensors of the present invention will serve as a significantly more accurate and effective measure of cell electric charge than the conventional electrophoresis technique that is known in the art because electrophoretic measurements suffer from a complicated instrumental dependence and a lack of spatial resolution.

[0018]The inventors herein further believe that the use of nanoscale EMR sensors in an imaging array will produce ultra high resolution images of magnetoresistance over the surface of one or more living cells, a result that can provide valuable information for studying the magnetic fields produced by nonmagnetic particles embedded in cancer cells, for monitoring magnetically labeled nanoparticles that are trafficking inside the cells or for sensing the evolution of imposed magnetic resonance spin orientations.

Problems solved by technology

A challenge has now presented itself with respect to how these large volumes of information can be integrated into an accurate model of cellular behavior and processes.

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